Project summary: This proposal describes a 3 year program for the development of the candidate as an independent investigator in Tumor Biology. In addition to completing a Ph.D. in Molecular Biology at the University of Pittsburgh, the candidate has completed residency training in Anatomic Pathology, a year-long fellowship in Liver and Gastrointestinal Pathology, and has practiced Liver and Gastrointestinal Pathology for almost three years at the University of California at Los Angeles. During this time he has engaged in postdoctoral basic research in the laboratory of Dr. Michael Teitell studying the regulation of the oncogene TCL1 and its role in carcinogenesis. This proposed program will allow the candidate to develop an independent research program beyond the scope of TCL1. The research will focus on the role that a newly identified mitochondrial exoribonuclease, PNPase, plays in TCL1-mediated malignant transformation. Recent work in the Teitell lab helped characterize a new TCL1 transgenic mouse model that develops distinct types of mature B-cell malignancies from germinal center B-cells. This model shows an increased activation of an essential proliferation and cell survival protein kinase, AKT, highlighting a potential mechanism in TCL1-mediated tumor formation. More recently, the candidate identified a third protein, termed polynucleotide phosphorylase (PNPase), that directly binds TCL1. The proposed experiments will involve determination of the role PNPase plays in the signaling pathway of TCL1/AKT mediated transformation as well as defining the unique biology of PNPase itself as it related to TCL1. This will provide a firm, separate foundation of work for the candidate to function as an researcher. The specific aims include: 1) Determining the role of PNPase in TCL1/AKT complex formation and AKT activation; 2) Determining the effects of TCL1/PNPase complex formation; and 3) Determining the effect of TCL1/PNPase on gene regulation. Relevance: One of the ways that cancer develops is through changes in levels and activity of the components of the communication system within a cell that determines whether it grows, stops growing, or dies. This study will allow for understanding the mechanism by which one of these cell components, TCL1, signals a cell to become cancerous in its interaction with a newly identified signaling component PNPase. [unreadable] [unreadable] [unreadable]